Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives

Abstract

Fibrous dysplasia (FD) is an uncommon and debilitating skeletal disorder resulting in fractures, deformity, functional impairment, and pain. It arises from post-zygotic somatic activating mutations in GNAS, in the cAMP-regulating transcript α-subunit, Gsα. Constitutive Gs signaling results in activation of adenylyl cyclase and dysregulated cAMP production. In the skeleton, this leads to the development of FD lesions with abnormal bone matrix, trabeculae, and collagen, produced by undifferentiated mesenchymal cells. FD may occur in isolation or in combination with extraskeletal manifestations, including hyperfunctioning endocrinopathies and café-au-lait macules, termed McCune-Albright syndrome (MAS). This review summarizes current clinical and translational perspectives in FD/MAS, with an emphasis on FD pathogenesis, natural history, pre-clinical and clinical investigation, and future directions.

Keywords: FGF23; Fibrous dysplasia; GNAS gene; Gsα; McCune-Albright syndrome.

Figure 1. Mosaicism in fibrous dysplasia/McCune-Albright syndrome

Panels A and B show ⁹⁹technetium bone scintrigraphy studies. Note physiologic bilateral tracer uptake in growth plates in the extremities and ribs. Additional areas of tracer uptake correspond to FD lesions, which range from mild (panel A, limited to the skull and left femur) to severe (panel B, involving the majority of the skeleton). Note the presence of scoliosis and a right-sided coxa vara (“shepherd’s crook”) deformity in panel B (red arrowheads). Panels C and D demonstrate typical café-au-lait macules, which tend to have jagged borders and reflect along the midline of the body, following patterns of embryonic cell migration. Macules occur along a broad spectrum, which may range from small subtle lesions (panel C, red arrowheads) to large areas of pigmentation with extensive truncal involvement (panel D).

Figure 2. Representative histologic features of fibrous dysplasia (FD)

A. FD lesions in the calvarium demonstrate typical complexes of bone trabeculae (b) embedded in areas of fibrous tissue (ft). B. Bone trabeculae (b) within areas of fibrous tissue (ft) demonstrate a typical discontinuous and parallel pattern. C. Morphologically atypical osteoblasts located along bone surfaces (asterisk). D. Collagen fibers perpendicularly oriented along forming bone surfaces, also termed Sharpey fibers (asterisk). E. Severe undermineralization of FD bone, as evidenced by excess osteoid (asterisk). F. In situ hybridization demonstrates FGF23 production by activated FD osteogenic cells.

Figure 3. Age-related radiographic features of fibrous dysplasia (FD)

A. Radiograph from a 2-year-old demonstrates a typical heterogeneous-appearing FD lesion in the proximal femur. B. Radiograph from an 11-year-old shows a characteristic “ground glass” lesion, which appears homogeneous and radiolucent. C. Radiograph from a 57-year-old demonstrates the tendency of FD to become more heterogenous and sclerotic over time. D. Head computed tomography from an 11-year-old shows diffuse FD involvement with homogenous “ground glass” appearance. E. Head computed tomography from a 54-year-old demonstrates the tendency for FD to become more heterogeneous, with focal areas of lucency throughout.